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1.
Int J Mol Sci ; 21(15)2020 Aug 02.
Article in English | MEDLINE | ID: mdl-32748831

ABSTRACT

It is well known that long-term consolidation of newly acquired information, including information related to social fear, require de novo protein synthesis. However, the temporal dynamics of protein synthesis during the consolidation of social fear memories is unclear. To address this question, mice received a single systemic injection with the protein synthesis inhibitor, anisomycin, at different time-points before or after social fear conditioning (SFC), and memory was assessed 24 h later. We showed that anisomycin impaired the consolidation of social fear memories in a time-point-dependent manner. Mice that received anisomycin 20 min before, immediately after, 6 h, or 8 h after SFC showed reduced expression of social fear, indicating impaired social fear memory, whereas anisomycin caused no effects when administered 4 h after SFC. These results suggest that consolidation of social fear memories requires two stages of protein synthesis: (1) an initial stage starting during or immediately after SFC, and (2) a second stage starting around 6 h after SFC and lasting for at least 5 h.


Subject(s)
Anisomycin/pharmacology , Fear/drug effects , Memory/drug effects , Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Animals , Anisomycin/administration & dosage , Conditioning, Classical/drug effects , Male , Mice , Protein Synthesis Inhibitors/administration & dosage , Time Factors
2.
Sci Rep ; 9(1): 7368, 2019 05 14.
Article in English | MEDLINE | ID: mdl-31089188

ABSTRACT

We collected 60 age-dependent transcriptomes for C. elegans strains including four exceptionally long-lived mutants (mean adult lifespan extended 2.2- to 9.4-fold) and three examples of lifespan-increasing RNAi treatments. Principal Component Analysis (PCA) reveals aging as a transcriptomic drift along a single direction, consistent across the vastly diverse biological conditions and coinciding with the first principal component, a hallmark of the criticality of the underlying gene regulatory network. We therefore expected that the organism's aging state could be characterized by a single number closely related to vitality deficit or biological age. The "aging trajectory", i.e. the dependence of the biological age on chronological age, is then a universal stochastic function modulated by the network stiffness; a macroscopic parameter reflecting the network topology and associated with the rate of aging. To corroborate this view, we used publicly available datasets to define a transcriptomic biomarker of age and observed that the rescaling of age by lifespan simultaneously brings together aging trajectories of transcription and survival curves. In accordance with the theoretical prediction, the limiting mortality value at the plateau agrees closely with the mortality rate doubling exponent estimated at the cross-over age near the average lifespan. Finally, we used the transcriptomic signature of age to identify possible life-extending drug compounds and successfully tested a handful of the top-ranking molecules in C. elegans survival assays and achieved up to a +30% extension of mean lifespan.


Subject(s)
Caenorhabditis elegans/physiology , Gene Regulatory Networks/genetics , Longevity/genetics , Transcriptome/genetics , Animals , Anisomycin/administration & dosage , Azacitidine/administration & dosage , Benzazepines/administration & dosage , Caenorhabditis elegans/drug effects , Caenorhabditis elegans Proteins/genetics , Camptothecin/administration & dosage , Datasets as Topic , Dipyrone/administration & dosage , Dose-Response Relationship, Drug , Gene Regulatory Networks/drug effects , Indoles/administration & dosage , Kaplan-Meier Estimate , Longevity/drug effects , Models, Animal , RNA-Seq , Time Factors
3.
Neurobiol Learn Mem ; 145: 151-164, 2017 Nov.
Article in English | MEDLINE | ID: mdl-29030298

ABSTRACT

Consolidated memories can become destabilized during reactivation, resulting in a transient state of instability, a process that has been hypothesized to underlie long-term memory updating. Consistent with this notion, relatively remote memories, which are resistant to standard destabilization procedures, are reliably destabilized when novel information (i.e., the opportunity for memory updating) is present during reactivation. We have also shown that cholinergic muscarinic receptor (mAChR) activation can similarly destabilize consolidated object memories. Synaptic protein degradation via the ubiquitin proteasome system (UPS) has previously been linked to destabilization of fear and object-location memories. Given the role of calcium in regulating proteasome activity, we hypothesized that activation of cholinergic receptors, specifically M1 mAChRs, stimulates the UPS via inositol triphosphate receptor (IP3R)-mediated release of intracellular calcium stores to facilitate object memory destabilization. We present converging evidence for this hypothesis, which we tested using a modified spontaneous object recognition task for rats and microinfusions into perirhinal cortex (PRh), a brain region strongly implicated in object memory. We extend our previous findings by demonstrating that M1 mAChRs are necessary for novelty-induced object memory destabilization. We also show that proteasome inhibition or IP3R antagonism in PRh prevents object memory destabilization induced by novelty or M1 mAChR stimulation. These results establish an intracellular pathway linking M1 receptors, IP3Rs, and UPS activity to object memory destabilization and suggest a previously unacknowledged role for cholinergic signaling in long-term memory modification and storage.


Subject(s)
Memory, Long-Term/physiology , Perirhinal Cortex/metabolism , Proteasome Endopeptidase Complex/metabolism , Receptor, Muscarinic M1/metabolism , Animals , Anisomycin/administration & dosage , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Male , Protein Synthesis Inhibitors/administration & dosage , Rats, Long-Evans , Recognition, Psychology/physiology , Ubiquitin/metabolism
4.
Neurobiol Learn Mem ; 144: 155-165, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28733208

ABSTRACT

Many studies suggest that fear conditioning influences sleep. It is, however, not known if the changes in sleep architecture after fear conditioning are essentially associated with the consolidation of fearful memory or with fear itself. Here, we have observed that within sleep, NREM sleep consistently remained augmented after the consolidation of cued fear-conditioned memory. But a similar change did not occur after impairing memory consolidation by blocking new protein synthesis and glutamate transmission between glial-neuronal loop in the lateral amygdala (LA). Anisomycin (a protein synthesis inhibitor) and DL-α-amino-adipic acid (DL- α -AA) (a glial glutamine synthetase enzyme inhibitor) were microinjected into the LA soon after cued fear-conditioning to induce memory impairment. On the post-conditioning day, animals in both the groups exhibited significantly less freezing. In memory-consolidated groups (vehicle groups), NREM sleep significantly increased during 2nd to 5th hours after training compared to their baseline days. However, in memory impaired groups (anisomycin and DL- α -AA microinjected groups), similar changes were not observed. Our results thus suggest that changes in sleep architecture after cued fear-conditioning are indeed a consolidation dependent event.


Subject(s)
Conditioning, Classical/physiology , Fear , Memory Consolidation/physiology , Sleep Stages , Animals , Anisomycin/administration & dosage , Avoidance Learning , Basolateral Nuclear Complex/drug effects , Male , Rats, Wistar , Wakefulness
5.
Biomed Res Int ; 2017: 3524307, 2017.
Article in English | MEDLINE | ID: mdl-28349059

ABSTRACT

Osteoporosis is a common disease causing fracture in older populations. Abnormal apoptosis of osteoblasts contributes to the genesis of osteoporosis. Inhibiting apoptosis of osteoblasts provides a promising strategy to prevent osteoporosis. The proliferation of osteoblasts isolated from osteoporotic patients or healthy subjects was determined by MTT assay. Apoptosis was determined by Annexin V/PI assay. Protein expression was measured by western blot. The proliferation of osteoblasts isolated from osteoporotic patients was inhibited and the apoptosis level of these cells was higher than the osteoblasts from healthy subjects. Incubation with psoralen or estradiol significantly enhanced the proliferation and decreased the apoptosis level of osteoporotic osteoblasts. Western blot demonstrated that psoralen or estradiol treatment downregulated the expression of IRE1, p-ASK, p-JNK, and Bax. Meanwhile, expression of Bcl-2 was upregulated. Pretreatment by IRE1 agonist tunicamycin or JNK agonist anisomycin attenuated the effect of psoralen on osteoporotic osteoblasts. Psoralen inhibited apoptosis of osteoporotic osteoblasts by regulating IRE1-ASK1-JNK pathway.


Subject(s)
Endoribonucleases/genetics , Ficusin/administration & dosage , MAP Kinase Kinase 4/genetics , MAP Kinase Kinase Kinase 5/genetics , Osteoporosis/drug therapy , Protein Serine-Threonine Kinases/genetics , Anisomycin/administration & dosage , Apoptosis/drug effects , Cell Differentiation/genetics , Cell Proliferation/drug effects , Endoribonucleases/biosynthesis , Female , Gene Expression Regulation/drug effects , Humans , MAP Kinase Kinase 4/biosynthesis , MAP Kinase Kinase Kinase 5/biosynthesis , MAP Kinase Signaling System/drug effects , Middle Aged , Osteoblasts/drug effects , Osteoporosis/genetics , Osteoporosis/pathology , Primary Cell Culture , Protein Serine-Threonine Kinases/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Tunicamycin/administration & dosage , bcl-2-Associated X Protein/biosynthesis
6.
Anticancer Drugs ; 28(2): 180-186, 2017 02.
Article in English | MEDLINE | ID: mdl-27879498

ABSTRACT

Renal cell carcinoma (RCC) is one of the most drug-resistant malignancies, and an effective therapy is lacking for metastatic RCC. Anisomycin is known to inhibit protein synthesis and induce ribotoxic stress. The aim of this study was to explore whether anisomycin enhances the cytotoxic effects of mapatumumab, a human agonistic monoclonal antibody specific for death receptor 4 (DR4), in human RCC cells. We examined the cytotoxicity of anisomycin alone and in combination with mapatumumab in human RCC cell lines and primary RCC cell cultures. RCC cells treated with anisomycin showed cytotoxicity in a dose-dependent manner. Anisomyin in combination with mapatumumab showed a synergistic effect not only in two human RCC cell lines but also in five primary RCC cell cultures. The synergy between anisomycin and mapatumumab for cytotoxicity was also observed for apoptosis. Interestingly, anisomycin significantly increased DR4 expression at both the mRNA and the protein level. Furthermore, the combination-induced cytotoxicity was significantly suppressed by a human recombinant DR4:Fc chimeric protein. The combination of anisomycin and mapatumumab also enhanced the activity of caspases 8 and 3, the downstream molecules of death receptors. These findings indicate that anisomycin sensitizes RCC cells to DR4-mediated apoptosis through the induction of DR4, suggesting that combinational treatment with anisomycin and mapatumumab might represent a novel therapeutic strategy for the treatment of RCC.


Subject(s)
Anisomycin/pharmacology , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Anisomycin/administration & dosage , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Caspase 3/metabolism , Caspase 8/metabolism , Cell Line, Tumor , Drug Synergism , Enzyme Activation/drug effects , Humans , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology
7.
Neurosci Lett ; 630: 222-227, 2016 Sep 06.
Article in English | MEDLINE | ID: mdl-27497918

ABSTRACT

The terrestrial slug Limax can form an odor-aversion memory by the single simultaneous presentation of a food odor and an aversive stimulus. We have previously demonstrated that the long-term retention of this memory was impaired by a high-dose injection of a protein synthesis inhibitor 30min prior to the conditioning. However, the onset of amnesia was delayed if the dose of the inhibitor was reduced or a less potent protein synthesis inhibitor was used. We thus speculated that the persistence of memory depends on the amount of newly synthesized protein following learning. In the present study, we further elaborated on this idea by injecting a high dose of anisomycin at different timings before or after conditioning, and tested the memory retention at 1, 2, 3, 7, or 14days after the conditioning. We found that the injection of anisomycin 6h before, or 1h after the conditioning had no effect on memory retention for 7days, and an injection at 30min before and just following the conditioning impaired the memory retention at 3days. Interestingly, the injection at 3h before and 30min after the conditioning did not impair the retention at 3days but did impair retention at 7days. Taking into account the time course of protein synthesis inhibition in the brain, our results further support the idea that the memory retention period is dependent on the amount of protein synthesized following memory acquisition.


Subject(s)
Memory, Long-Term/physiology , Protein Biosynthesis , Retention, Psychology/physiology , Amnesia/chemically induced , Amnesia/physiopathology , Animals , Anisomycin/administration & dosage , Avoidance Learning/drug effects , Avoidance Learning/physiology , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Gastropoda , Memory, Long-Term/drug effects , Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/administration & dosage , Retention, Psychology/drug effects
8.
Learn Mem ; 23(9): 486-93, 2016 09.
Article in English | MEDLINE | ID: mdl-27531839

ABSTRACT

Destabilization refers to a memory that becomes unstable when reactivated and is susceptible to disruption by amnestic agents. Here we delineated the cellular mechanism underlying the destabilization of drug memory. Mice were conditioned with methamphetamine (MeAM) for 3 d, and drug memory was assessed with a conditioned place preference (CPP) protocol. Anisomycin (ANI) was administered 60 min after the CPP retrieval to disrupt reconsolidation. We found that destabilization of MeAM CPP after the application of ANI was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 and the NR2B antagonist ifenprodil (IFN) but not by the NR2A antagonist NVP-AAM077 (NVP). In addition, decrease in the phosphorylation of GluR1 at Serine845 (p-GluR1-Ser845), decrease in spine density, and a reduction in the AMPAR/NMDAR ratio in the basolateral amygdala (BLA) were reversed after the MK-801 treatment. The effect of ANI on destabilization was prevented by the protein phosphatase 2B (calcineurin, CaN) inhibitors cyclosporine A (CsA) and FK-506 and the protein phosphatase 1 (PP1) inhibitors calyculin A (CA) and okadaic acid (OA). These results suggest that memory destabilization involves the activation of NR2B-containing NMDARs, which in turn allows the influx of Ca(2+) Increased intracellular Ca(2+) stimulates CaN, leading to the dephosphorylation and inactivation of inhibitor 1 and the activation of PP1. PP1 then dephosphorylates p-GluR1-Ser845 to elicit AMPA receptor (AMPAR) endocytosis and destabilization of the drug memory.


Subject(s)
Amygdala/enzymology , Memory Consolidation/physiology , Methamphetamine/administration & dosage , Phosphoprotein Phosphatases/physiology , Amygdala/drug effects , Animals , Anisomycin/administration & dosage , Calcium Signaling/drug effects , Conditioning, Classical , Dendritic Spines/drug effects , Dendritic Spines/physiology , Dizocilpine Maleate/administration & dosage , Male , Memory Consolidation/drug effects , Mental Recall/drug effects , Mental Recall/physiology , Mice, Inbred C57BL , Phosphoprotein Phosphatases/antagonists & inhibitors , Protein Synthesis Inhibitors/administration & dosage , Quinoxalines/administration & dosage , Receptors, AMPA/physiology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology
9.
Biochem Biophys Res Commun ; 478(1): 481-485, 2016 09 09.
Article in English | MEDLINE | ID: mdl-27404124

ABSTRACT

Transcription factor GATA-6 plays a key role in normal cell differentiation of the mesoderm and endoderm. On the other hand, GATA-6 is abnormally overexpressed in many clinical gastrointestinal cancer tissue samples, and accelerates cell proliferation or an anti-apoptotic response in cancerous tissues. We previously showed that activation of the JNK signaling cascade causes proteolysis of GATA-6. In this study, we demonstrated that anisomycin, a JNK activator, stimulates nuclear export of GATA-6 in a colorectal cancer cell line, DLD-1. Concomitantly, anisomycin remarkably inhibits the proliferation of DLD-1 cells via G2/M arrest in a plate culture. However, it did not induce apoptosis under growth arrest conditions. Furthermore, the growth of DLD-1 cells in a spheroid culture was suppressed by anisomycin. Although 5-FU showed only a slight inhibitory effect on 3D spheroid cultures, the same concentration of 5-FU together with a low concentration of anisomycin exhibited strong growth inhibition. These results suggest that the induction of GATA-6 dysfunction may be more effective for chemotherapy for colorectal cancer, although the mechanism underlying the synergistic effect of 5-FU and anisomycin remains unknown.


Subject(s)
Anisomycin/administration & dosage , Cell Proliferation/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Fluorouracil/administration & dosage , GATA6 Transcription Factor/metabolism , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Colorectal Neoplasms/pathology , Drug Synergism , Humans , Protein Synthesis Inhibitors/administration & dosage
10.
PLoS One ; 11(6): e0157859, 2016.
Article in English | MEDLINE | ID: mdl-27314672

ABSTRACT

Neuroplasticity and reorganization of brain motor networks are thought to enable recovery of motor function after ischemic stroke. Especially in the cortex surrounding the ischemic scar (i.e., peri-infarct cortex), evidence for lasting reorganization has been found at the level of neurons and networks. This reorganization depends on expression of specific genes and subsequent protein synthesis. To test the functional relevance of the peri-infarct cortex for recovery we assessed the effect of protein synthesis inhibition within this region after experimental stroke. Long-Evans rats were trained to perform a skilled-reaching task (SRT) until they reached plateau performance. A photothrombotic stroke was induced in the forelimb representation of the primary motor cortex (M1) contralateral to the trained paw. The SRT was re-trained after stroke while the protein synthesis inhibitor anisomycin (ANI) or saline were injected into the peri-infarct cortex through implanted cannulas. ANI injections reduced protein synthesis within the peri-infarct cortex by 69% and significantly impaired recovery of reaching performance through re-training. Improvement of motor performance within a single training session remained intact, while improvement between training sessions was impaired. ANI injections did not affect infarct size. Thus, protein synthesis inhibition within the peri-infarct cortex impairs recovery of motor deficits after ischemic stroke by interfering with consolidation of motor memory between training sessions but not short-term improvements within one session.


Subject(s)
Motor Cortex/physiopathology , Motor Skills/physiology , Neurons/pathology , Stroke/drug therapy , Animals , Anisomycin/administration & dosage , Disease Models, Animal , Forelimb/drug effects , Forelimb/physiopathology , Gene Expression Regulation/drug effects , Humans , Motor Cortex/drug effects , Motor Skills/drug effects , Nerve Net/drug effects , Nerve Net/physiopathology , Neuronal Plasticity/drug effects , Neurons/drug effects , Protein Biosynthesis/drug effects , Rats , Recovery of Function , Stroke/physiopathology , Stroke Rehabilitation
11.
Neurobiol Learn Mem ; 133: 129-135, 2016 09.
Article in English | MEDLINE | ID: mdl-27311758

ABSTRACT

Conditioned responses gradually weaken and eventually disappear when subjects are repeatedly exposed to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US), a process called extinction. Studies have demonstrated that extinction of conditioned taste aversion (CTA) can be prevented by interfering with protein synthesis in the insular cortex (IC). However, it remained unknown whether it is possible to pharmacologically stabilize the taste aversive memory trace over longer periods of time. Thus, the present study aimed at investigating the time frame during which extinction of CTA can be efficiently prevented by blocking protein synthesis in the IC. Employing an established conditioning paradigm in rats with saccharin as CS, and the immunosuppressant cyclosporine A (CsA) as US, we show here that daily bilateral intra-insular injections of the protein synthesis inhibitor anisomycin (120µg/µl) immediately after retrieval significantly diminished CTA extinction over a period of five retrieval days and subsequently reached levels of saline-infused controls. These findings demonstrate that it is possible to efficiently delay but not to fully prevent CTA extinction during repeated retrieval trials by blocking protein translation with daily bilateral infusions of anisomycin in the IC. These data confirm and extent earlier reports indicating that the role of protein synthesis in CTA extinction learning is not limited to gastrointestinal malaise-inducing drugs such as lithium chloride (LiCl).


Subject(s)
Anisomycin/pharmacology , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Conditioning, Classical/drug effects , Cyclosporine/pharmacology , Extinction, Psychological/drug effects , Immunosuppressive Agents/pharmacology , Mental Recall/drug effects , Protein Biosynthesis/drug effects , Protein Synthesis Inhibitors/pharmacology , Animals , Anisomycin/administration & dosage , Cyclosporine/administration & dosage , Immunosuppressive Agents/administration & dosage , Male , Protein Synthesis Inhibitors/administration & dosage , Rats , Time Factors
12.
Neurobiol Learn Mem ; 131: 18-25, 2016 05.
Article in English | MEDLINE | ID: mdl-26968655

ABSTRACT

Spermidine (SPD) is an endogenous aliphatic amine that modulates GluN2B-containing NMDA receptors and improves memory. Recent evidence suggests that systemic SPD improves the persistence of the long term memory of fear. However, the role of hippocampal polyamines and its binding sites in the persistence of fear memory is to be determined, as well as its putative underlying mechanisms. This study investigated whether the intrahippocampal (i.h.) infusion of spermidine or arcaine, modulators of polyamine binding site at GluN2B-containing NMDA receptors, alters the persistence of the memory of contextual fear conditioning task in rats. We also investigated whether protein synthesis and cAMP dependent protein kinase (PKA) play a role in SPD-induced improvement of the fear memory persistence. While 12h post-training infusion of spermidine facilitated, arcaine and the inhibitor of protein synthesis (anisomycin) impaired the memory of fear assessed 7days after training. The infusion of arcaine, anisomycin or a selective PKA inhibitor (H-89), at doses that have no effect on memory per se, prevented the SPD-induced improvement of memory persistence. H-89 prevented the stimulatory effect of SPD on phospho-PKA/total-PKA ratio. These results suggests that the improvement of fear memory persistence induced by spermidine involves GluN2B-containing NMDA receptors, PKA pathway and protein synthesis in rats.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Fear/physiology , Hippocampus/drug effects , Memory, Long-Term/drug effects , Nootropic Agents/pharmacology , Polyamines/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Synthesis Inhibitors/pharmacology , Spermidine/pharmacology , Animals , Anisomycin/administration & dosage , Anisomycin/pharmacology , Behavior, Animal/drug effects , Behavior, Animal/physiology , Biguanides/administration & dosage , Biguanides/pharmacology , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Isoquinolines/administration & dosage , Isoquinolines/pharmacology , Male , Nootropic Agents/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Protein Synthesis Inhibitors/administration & dosage , Rats , Rats, Wistar , Spermidine/administration & dosage , Sulfonamides/administration & dosage , Sulfonamides/pharmacology
13.
Oncol Rep ; 35(4): 1916-24, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26783004

ABSTRACT

Human ovarian cancer stem cells (OCSCs) are one of the main factors affecting ovarian cancer cell metastasis, recurrence, prognosis and tolerance to chemotherapy drugs. However, the mechanisms of OCSC proliferation and invasion are not clear. Recent studies suggest that anisomycin can inhibit the proliferative and invasive ability of various tumor cells by increasing the production of the toxic amyloid ß (Aß1-42) peptides from the amyloid precursor protein (APP). We explored whether anisomycin could also suppress human OCSC proliferation and invasion. The CD44+/CD117+ OCSCs were enriched from human clinical ovarian tumor tissues. OCSCs treated with anisomycin showed reduced proliferation compared to controls. Moreover, anisomycin significantly suppressed the invasive capacity of OCSCs in vitro, as indicated by cell migration assays. The mRNA expression levels of long non-coding RNA (lncRNA) ß-site APP cleaving enzyme 1 antisense strand (BACE1-AS) were significantly increased in anisomycin-treated OCSCs compared to controls. In addition, mRNA and protein levels of BACE1 and Aß1-42 were increased in anisomycin-treated OCSCs compared to controls. We confirmed that anisomycin suppressed the growth of xenograft tumors formed by OCSCs in vivo. Finally, when expression of lncRNA BACE1-AS was silenced using siRNA, BACE1 expression was downregulated and the antiproliferative and anti-invasive effects of anisomycin were reduced. Overall, we identified lncRNA BACE1-AS as a novel target for anisomycin. Elevation of lncRNA BACE1-AS expression is a potential mechanism for suppressing human OCSC proliferation and invasion.


Subject(s)
Anisomycin/administration & dosage , Neoplastic Stem Cells/drug effects , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , RNA, Long Noncoding/genetics , Adult , Animals , Anisomycin/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Mice , Middle Aged , Neoplasm Invasiveness , Up-Regulation , Xenograft Model Antitumor Assays
14.
Neuropharmacology ; 105: 10-14, 2016 06.
Article in English | MEDLINE | ID: mdl-26792192

ABSTRACT

Relief learning refers to the association of a stimulus with the relief from an aversive event. The thus-learned relief stimulus then can induce, e.g., an attenuation of the startle response or approach behavior, indicating positive valence. Previous studies revealed that the nucleus accumbens is essential for the acquisition and retrieval of relief memory. Here, we ask whether the nucleus accumbens is also the brain site for consolidation of relief memory into a long-term form. In rats, we blocked local protein synthesis within the nucleus accumbens by local infusions of anisomycin at different time points during a relief conditioning experiment. Accumbal anisomycin injections immediately after the relief conditioning session, but not 4 h later, prevented the consolidation into long-term relief memory. The retention of already consolidated relief memory was not affected by anisomycin injections. This identifies a time window and site for relief memory consolidation. These findings should complement our understanding of the full range of effects of adverse experiences, including cases of their distortion in humans such as post-traumatic stress disorder and/or phobias.


Subject(s)
Adaptation, Psychological/physiology , Memory Consolidation/physiology , Nucleus Accumbens/physiology , Protein Biosynthesis , Animals , Anisomycin/administration & dosage , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Male , Memory Consolidation/drug effects , Memory, Long-Term/drug effects , Memory, Long-Term/physiology , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Protein Synthesis Inhibitors/administration & dosage , Rats , Rats, Sprague-Dawley , Reflex, Startle/drug effects
15.
Proc Natl Acad Sci U S A ; 112(2): E230-3, 2015 Jan 13.
Article in English | MEDLINE | ID: mdl-25550507

ABSTRACT

In the present study we test the hypothesis that extinction is not a consequence of retrieval in unreinforced conditioned stimulus (CS) presentation but the mere perception of the CS in the absence of a conditioned response. Animals with cannulae implanted in the CA1 region of hippocampus were subjected to extinction of contextual fear conditioning. Muscimol infused intra-CA1 before an extinction training session of contextual fear conditioning (CFC) blocks retrieval but not consolidation of extinction measured 24 h later. Additionally, this inhibition of retrieval does not affect early persistence of extinction when tested 7 d later or its spontaneous recovery after 2 wk. Furthermore, both anisomycin, an inhibitor of ribosomal protein synthesis, and rapamycin, an inhibitor of extraribosomal protein synthesis, given into the CA1, impair extinction of CFC regardless of whether its retrieval was blocked by muscimol. Therefore, retrieval performance in the first unreinforced session is not necessary for the installation, maintenance, or spontaneous recovery of extinction of CFC.


Subject(s)
Extinction, Psychological/physiology , Learning/physiology , Animals , Anisomycin/administration & dosage , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/physiology , Conditioning, Psychological/physiology , Extinction, Psychological/drug effects , Fear/physiology , Fear/psychology , GABA-A Receptor Agonists/administration & dosage , Learning/drug effects , Male , Models, Neurological , Models, Psychological , Muscimol/administration & dosage , Protein Synthesis Inhibitors/administration & dosage , Rats , Rats, Wistar , Sirolimus/administration & dosage
16.
Tissue Cell ; 47(1): 1-9, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25435485

ABSTRACT

To investigate the involvement of stress-activated protein kinases, JNK and p38 MAPK, in the assembly of tight junctions in keratinocytes, we treated HaCaT cells with various combinations of SP600125 (an inhibitor of JNK), SB202190 (an inhibitor of p38 MAPK) and anisomycin (an activator of both JNK and p38 MAPK) and examined the localization of ZO-1, an undercoat constitutive protein of the tight junction. Short-term (8h) incubation with SP600125, SB202190 or anisomycin induced the accumulation of ZO-1 in the cell-cell contacts, with reduced ZO-1 staining in the cytoplasm, while only long-term (24h) incubation with SP600125 induced the accumulation of ZO-1. SP600125, SB202190 or SP600125 plus SB202190 treatment induced thin linear staining for ZO-1 in the cell-cell contacts. Anisomycin treatment induced thick and irregular linear staining for ZO-1, while anisomycin plus SP600125 treatment induced zipper-like staining for ZO-1. Anisomycin plus SB202190 treatment or anisomycin plus both SP600125 and SB202190 treatment for 8h failed to lead to the accumulation of ZO-1 in cell-cell contacts, but induced thin linear staining with several gaps 16 h after removal of these agents. These results suggest that the localization of ZO-1 in cell-cell contacts is differently regulated by activation and inhibition of JNK and/or p38 MAPK depending on the incubation period.


Subject(s)
JNK Mitogen-Activated Protein Kinases/metabolism , Zonula Occludens-1 Protein/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Anisomycin/administration & dosage , Anthracenes/administration & dosage , Cell Communication/drug effects , Cell Line , Humans , Imidazoles/administration & dosage , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Keratinocytes/drug effects , Keratinocytes/metabolism , Phosphorylation , Pyridines/administration & dosage , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
17.
Nat Neurosci ; 17(8): 1043-5, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24997764

ABSTRACT

Hyperalgesia arising from sensitization of pain relays in the spinal dorsal horn shares many mechanistic and phenotypic parallels with memory formation. We discovered that mechanical hyperalgesia could be rendered labile and reversible in mice after reactivation of spinal pain pathways in a process analogous to memory reconsolidation. These findings reveal a previously unknown regulatory mechanism underlying hyperalgesia and demonstrate the existence of reconsolidation-like processes in a sensory system.


Subject(s)
Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , Memory/physiology , Protein Synthesis Inhibitors/pharmacology , Sensory System Agents/pharmacology , Spinal Cord/physiopathology , Animals , Anisomycin/administration & dosage , Anisomycin/pharmacology , Capsaicin/administration & dosage , Capsaicin/pharmacology , Central Nervous System Sensitization/drug effects , Central Nervous System Sensitization/physiology , Disease Models, Animal , Hyperalgesia/chemically induced , Male , Mice , Mice, Inbred C57BL , Pain/chemically induced , Pain/drug therapy , Pain/physiopathology , Posterior Horn Cells/drug effects , Posterior Horn Cells/physiopathology , Protein Synthesis Inhibitors/administration & dosage , Sensory System Agents/administration & dosage , Spinal Cord/cytology , Spinal Cord/pathology
18.
Proc Natl Acad Sci U S A ; 111(12): 4572-7, 2014 Mar 25.
Article in English | MEDLINE | ID: mdl-24591622

ABSTRACT

Exposure to a novel environment enhances the extinction of contextual fear. This has been explained by tagging of the hippocampal synapses used in extinction, followed by capture of proteins from the synapses that process novelty. The effect is blocked by the inhibition of hippocampal protein synthesis following the novelty or the extinction. Here, we show that it can also be blocked by the postextinction or postnovelty intrahippocampal infusion of the NMDA receptor antagonist 2-amino-5-phosphono pentanoic acid; the inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII), autocamtide-2-related inhibitory peptide; or the blocker of L-voltage-dependent calcium channels (L-VDCCs), nifedipine. Inhibition of proteasomal protein degradation by ß-lactacystin has no effect of its own on extinction or on the influence of novelty thereon but blocks the inhibitory effects of all the other substances except that of rapamycin on extinction, suggesting that their action depends on concomitant synaptic protein turnover. Thus, the tagging-and-capture mechanism through which novelty enhances fear extinction involves more molecular processes than hitherto thought: NMDA receptors, L-VDCCs, CaMKII, and synaptic protein turnover.


Subject(s)
Behavior, Animal , Fear , Hippocampus/physiology , Acetylcysteine/administration & dosage , Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Animals , Anisomycin/administration & dosage , Anisomycin/pharmacology , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/pharmacology , Conditioning, Classical , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Proteasome Endopeptidase Complex/metabolism , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Rats , Sirolimus/administration & dosage , Sirolimus/pharmacology , Ubiquitin/metabolism
19.
Leuk Lymphoma ; 55(9): 2179-88, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24597985

ABSTRACT

Glucocorticoid (GC) resistance in children with acute lymphoblastic leukemia (ALL) usually resulted in the failure of treatment. Exploring new agents to overcome GC resistance is important. Here we reported for the first time that low-dose anisomycin has the potential to sensitize GC-resistant T-ALL CEM-C1 cells to dexamethasone (DEX). Compared with the use of DEX or low-dose anisomycin alone, co-treatment with them resulted in a significant increase of growth inhibition, apoptosis and cell cycle arrest in CEM-C1 cells through induction of activated caspase-3 and up-regulation of Bim, p21and p27, and down-regulation of Mcl-1, Bcl-2, c-myc, cyclin A and cyclin D1. Furthermore, co-treatment remarkably activated glucocorticoid receptor (GR), p38-MAPK and JNK, and all of them were canceled only by the GR inhibitor RU486, indicating GR might be an at the upstream of GR-p38-MAPK/JNK pathway. We conclude that low-dose anisomycin sensitizes GC-resistant CEM-C1 cells to DEX and this effect is mediated, at least in part, by activation of the GR-p38-MAPK/JNK signaling pathway.


Subject(s)
Anisomycin/pharmacology , Apoptosis/drug effects , Dexamethasone/pharmacology , Drug Resistance, Neoplasm , Glucocorticoids/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Receptors, Glucocorticoid/agonists , p38 Mitogen-Activated Protein Kinases/metabolism , Anisomycin/administration & dosage , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Humans , Signal Transduction/drug effects
20.
Addict Biol ; 19(1): 5-15, 2014 Jan.
Article in English | MEDLINE | ID: mdl-22458530

ABSTRACT

Positive and negative emotional experiences induced by addictive drugs play an important role in the development of dysfunctional drug-related memory, which becomes resistant to extinction and contributes to high rate of relapse. Those memories may undergo a process called reconsolidation that in some cases can be disrupted by pharmacological treatment. The basolateral amygdala (BLA) has been shown to mediate the reconsolidation of drug-related appetitive memory, but its role in withdrawal-related aversive memory remains elusive. The present study used conditioned place preference (CPP) and conditioned place aversion (CPA) paradigms to investigate the role of BLA and its noradrenergic receptors in reconsolidation of morphine-associated emotional memory in rats. We found that inhibition of protein synthesis in BLA disrupted the reconsolidation of morphine CPP (m-CPP) and CPA related to morphine withdrawal (m-CPA). A high dose of the ß-noradrenergic receptor antagonist propranolol (3 µg) in BLA-impaired reconsolidation of m-CPA but not m-CPP, whereas a low dose (0.3 µg) was ineffective. In contrast, neither low nor high doses of the α-noradrenergic receptor antagonist phentolamine (1 or 10 µg) blocked the reconsolidation of m-CPP and m-CPA. In addition, infusion of propranolol (3 µg) into nucleus accumbens after retrieval of either m-CPP or m-CPA did not affect its reconsolidation. The findings indicate that appetitive and aversive addictive memories share common neural substrates in BLA, but the specific neurotransmitter mechanism on reconsolidation of morphine-associated negative and positive memories can be dissociable.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Amygdala/drug effects , Memory/physiology , Morphine/pharmacology , Narcotics/pharmacology , Propranolol/pharmacology , Receptors, Adrenergic, beta/physiology , Adrenergic alpha-Antagonists/administration & dosage , Adrenergic alpha-Antagonists/pharmacology , Adrenergic beta-Antagonists/administration & dosage , Amygdala/physiopathology , Analysis of Variance , Animals , Anisomycin/administration & dosage , Appetitive Behavior/drug effects , Appetitive Behavior/physiology , Avoidance Learning/drug effects , Avoidance Learning/physiology , Choice Behavior/drug effects , Conditioning, Psychological/physiology , Dose-Response Relationship, Drug , Male , Memory/drug effects , Microinjections , Morphine Dependence/psychology , Nucleus Accumbens/drug effects , Nucleus Accumbens/physiopathology , Phentolamine/administration & dosage , Phentolamine/pharmacology , Propranolol/administration & dosage , Protein Synthesis Inhibitors/administration & dosage , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, beta/drug effects , Recurrence , Substance Withdrawal Syndrome/psychology
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